Hyperphosphatemia occurs when the blood stores high levels of inorganic phosphate. This condition is prevalent in patients with severe kidney dysfunction, including chronic renal insufficiency and end stage renal disease. Similar to calcium, phosphate is found in bones and teeth and absorption occurs efficiently with consistent Vitamin D intake. Under normal conditions, the kidneys excrete phosphate. However in those patients with hyperphosphatemia, the kidneys are unable to remove the phosphate and dialysis proves to be ineffective in phosphate removal.
Patents with hyperphosphatemia often do not exhibit symptoms. Progressive bone weakness can occur however, resulting in pain and the bone's increased susceptibility to fractures and breaks. Phosphate that crystallizes in the walls of blood vessels and the heart can cause arteriosclerosis and lead to strokes, heart attacks, and poor circulation. Skin sensitivity can also occur if these phosphate crystals form in the skin.
Lanthanum carbonate is a known phosphate binder and is used to reduce phosphate levels in patients with hyperphosphatemia, and specifically, those patients with hyperphosphatemia caused by end stage renal disease. Reduction of serum phosphate and calcium phosphate is accomplished through lanthanum carbonate's inhibition of phosphate absorption through formation of insoluble lanthanum phosphate complexes. Furthermore, there has been a recent push to expand the labeled use of the phosphate binder to include the treatment of hyperphosphatemia in stage 4 chronic kidney disease patients. In October of 2007, the U.S. Food and Drug Administration's Cardiovascular and Renal Drugs Advisory Committee recommended the extension to include this broader use.
Lanthanum carbonate is currently available from Shire US Inc. in 500, 750, and 1000 mg chewable tablets, marketed under the trade name, Fosrenol®. The chewable tablets are the only dosage form available for patients. When placed in water, these tablets do not disintegrate, but remain as large granules, even after a period of many hours. The Fosrenol® chewable tablets are of substantial size, ranging in diameter from 18 mm for the 500 mg strength and 22 mm for the 1000 mg strength. Chewable tablets are often not ideal, as they can be difficult for patients to ingest and often have an unpleasant taste. Further, many patients, children and elderly in particular, often display difficulty in chewing such tablets thoroughly, leading to an inadequate therapeutic delivery. Phosphate uptake is dependent upon the surface area of the insoluble lanthanum carbonate particles. The surface area of the lanthanum carbonate depends upon the thoroughness of the patient's chewing, resulting in a wide variance of effectiveness of the actual ingested dose of active lanthanum carbonate. Therefore, increased dosages of Fosrenol® are often necessary to obtain effective levels of lanthanum carbonate.
U.S. Pat. No. 5,968,976 discloses a pharmaceutical composition for treating hyperphosphatemia comprised of lanthanum carbonate of the formula La2(CO3)3.xH2O, where x has a value from 3 to 6, in admixture with a pharmaceutically acceptable diluent or carrier, in a form for administration to the gastrointestinal tract. A process for its preparation is also disclosed and comprises oven drying lanthanum carbonate octahydrate to obtain the lanthanum carbonate with 3 to 6 moles of water. The patent does not disclose adequate means of oral delivery of the lanthanum carbonate for effective compliance and therapeutic delivery.
U.S. Pat. No. 7,381,428 discloses a method for treating hyperphosphatemia with a formulation comprising a lanthanum carbonate composition of La2(CO3)3.xH2O, wherein x equals between 0 and 10, and at least one monosaccharide or disaccharide stabilizer to stabilize the lanthanum carbonate against decarboxylation to lanthanum hydroxycarbonate. The patent does not disclose adequate means of oral delivery of the lanthanum carbonate for effective compliance and therapeutic delivery.
U.S. Pat. No. 7,465,465 discloses a chewable lanthanum formulation in a tablet comprising lanthanum and a chewable excipient. This application further discloses the lanthanum tablet formulation produced through a process of powder blending the lanthanum compound and an excipient in a mixer to form a mixture. The mixture is then either compressing into a slug material or roller compacting into a strand material. The compressed/compacted material is then milled into a free flowing mixture and compressed into a tablet. These formulations have the disclosed use of treatment for hyperphosphatemia. This representation of the current state of the art does not address the insufficiencies of these chewable tablets in patient compliance and therapeutic delivery.
United States Patent Application Publication Nos. 2004/0161474, 2006/0003018, 2006/0083791, and 2008/0226735 disclose lanthanum carbonate preparations with specific surface area to increase phosphate binding ability. The applications do not address suitable dosage forms to allow for better patient compliance and therapeutic delivery.
United States Patent Application Publication No. 2005/0208080 discloses a formulation of lanthanum carbonate in the form of a sandwich biscuit. This “cookie” has two or more layers that support an unpalatable medicament, i.e. lanthanum carbonate. The application, however, does not disclose a method of improving the phosphate binding of the lanthanum carbonate.
The current state of lanthanum carbonate pharmaceutical dosage forms are not sufficient. The considerable size of the chew tablets coupled with their unpleasant taste lead to poor patient compliance and inadequate therapeutic delivery.